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Anesth Analg 2001;93:1100-1105
© 2001 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

The Pharmacokinetics of Remifentanil in Patients Undergoing Coronary Artery Bypass Grafting with Cardiopulmonary Bypass

Luis G. Michelsen, MD*, Nicholas H. G. Holford, MB ChB{dagger}, Wei Lu, PhD*, John F. Hoke, PhD{ddagger}, Carl C. Hug, MD PhD*, and James M. Bailey, MD PhD*

*Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia; {dagger}Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand; and {ddagger}Department of Clinical Pharmacology, Glaxo, Inc., Research Triangle Park, North Carolina

Address correspondence to James M. Bailey, MD, PhD, Department of Anesthesiology, Emory University School of Medicine, 1364 Clifton Rd. NE, Atlanta, GA 30322. Address e-mail to james_bailey{at}emory.org


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Remifentanil is a potent opioid with a short duration of action. It has the potential for large-dose opioid anesthesia without an obligatory prolonged period of mechanical ventilation. However, because of high clearance and rapid tissue distribution, cardiopulmonary bypass (CPB) may influence its pharmacokinetics and alter drug requirements. We administered remifentanil by continuous infusion to 68 patients having coronary artery bypass graft surgery during CPB with hypothermia to describe the effects of these interventions on its pharmacokinetics. Remifentanil concentrations were measured before, during, and after CPB. Disposition was best described by a two-compartment model. The volume of distribution increased by 86% with institution of CPB and remained increased after CPB. Elimination clearance decreased by 6.37% for each degree Celsius decrease from 37°C.

IMPLICATIONS: Remifentanil concentrations decrease with the institution of cardiopulmonary bypass because of an increase in the volume of distribution. The decrease in elimination clearance with hypothermia results in increased total remifentanil concentrations during cardiopulmonary bypass if the infusion rate is not altered. More constant blood remifentanil levels may be obtained by reducing remifentanil infusion rate by 30% for each 5°C decrease in temperature.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
No study has identified an optimal anesthetic technique for cardiac surgical operations. Many clinicians prefer opioid-based anesthetics to avoid myocardial depression from volatile anesthetics while blunting the hemodynamic response to noxious stimuli (1–3). The doses of most opioids needed to achieve this goal result in large blood concentrations and prolonged respiratory depression requiring mechanical ventilation (4,5). In recent years, there has been a move toward volatile anesthetics that allow earlier recovery, and decrease intensive care unit stays (6–9). To maintain the hemodynamic stability and myocardial performance associated with large-dose opioid administration, and still allow rapid recovery, the ideal opioid should be rapidly titratable and nonaccumulating. Remifentanil is a potent µ-opioid receptor agonist with a very short elimination half-time because of rapid hydrolysis to a minimally active metabolite by nonspecific blood and tissue esterases (10–18). Remifentanil’s organ-independent biotransformation, and short half-life should make it an ideal drug to provide intense analgesia during surgery followed by rapid and predictable postoperative recovery.

However, effective use of remifentanil for this purpose requires an understanding of the pharmacokinetics of the drug during cardiac surgery. Cardiopulmonary bypass (CPB) may have significant effects on drug disposition because of hemodilution, altered regional blood flow, hypothermia, altered protein binding, heparin administration, uptake of drugs by the bypass circuit, and isolation of lungs from the circulation (19,20). To propose appropriate dosing strategies for the use of remifentanil during CPB cases, we have investigated the effect of CPB and hypothermia on the disposition of remifentanil in patients undergoing coronary artery bypass grafting surgery.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
This is a report of 68 patients included in a randomized, open-label, parallel-group study performed at three centers in the United States (Emory University Hospital, Ohio State University Hospital, and University of Cincinnati Medical Center). An IRB at each center approved the protocol and all patients provided written informed consent before participation. Patients were excluded from the study if they had any of the following: clinically significant dysrhythmia, severe or uncontrolled central nervous system, lung, liver, kidney, or endocrine disease; pulmonary edema or pleural effusion; congestive heart failure; emergency surgery (<6 h after failed coronary angioplasty); ejection fraction <35% or left ventricular stroke volume <50 mL; concurrent valve repair or replacement; myocardial infarction within 3 days; or ethanol or drug abuse.

All patients were premedicated with lorazepam 40 µg/kg, administered orally 2 h preoperatively, and received morphine 0.05 mg/kg and 1 or 2 doses of lorazepam 20 µg/kg IV for sedation during intravascular catheter placement, if needed.

Anesthesia was induced by a continuous IV infusion of remifentanil (1, 2, or 3 µg · kg-1 · min-1, randomly assigned) and tracheal intubation was facilitated with vecuronium 0.15 mg/kg. The following hemodynamic variables were recorded: heart rate, systemic blood pressure (systolic, mean, diastolic), pulmonary artery pressure (systolic, mean, diastolic), central venous pressure, and cardiac output. The remifentanil infusion rate was maintained at the initial rate unless signs of light anesthesia occurred in response to surgical stimuli. Light anesthesia was identified by a heart rate >90 bpm, systolic blood pressure >15 mm Hg above baseline, somatic body response (movement, swallowing, grimacing, or eye opening), or an autonomic response (tearing, sweating, mydriasis). Signs of light anesthesia were treated with bolus doses of remifentanil (1 or 2 µg/kg) or an increase in the infusion rate. If signs of light anesthesia persisted for >5 min after the infusion rate was increased to 2 µg · kg-1 · min-1 above the initial rate, isoflurane, 0.5%–1%, was administered as "rescue" anesthesia. The remifentanil infusion rate was reduced in decrements of 1 µg · kg-1 · min-1 back to the initial rate if hypotension occurred. Hypotension before and after CPB was defined as a reduction in systolic blood pressure of >=15 mm Hg. Persistent hypotension during CPB (mean arterial blood pressure <50 mm Hg for >10 min) was treated with one or two 50% decrements in the remifentanil infusion rate (to a minimal dose of 0.25 µg · kg-1 · min-1). At the end of CPB, the remifentanil infusion rate was restored to the pre-CPB rate in increments equal to the decrements by which it had been decreased.

CPB was conducted with varying degrees of hypothermia, depending on surgical preference, with {alpha}-stat pH management. The CPB prime was 1 L of crystalloid (PlasmalyteTM, Baxter, Deerfield, IL) and 500 mL of hetastarch, with 50 g of mannitol. The oxygenator was composed of a microporous flat polypropylene sheet from Cobe (Arvada, CO), tubing was polyvinyl chloride, and the venous reservoir was hard polycarbonate. The cardioplegia solution was a balanced crystalloid solution (Plasmalyte) with 3 mL of 50% dextrose and 20 mEq of sodium bicarbonate per liter, and a potassium concentration of 30 mEq/L. The initial dose was 30 mL/kg with subsequent doses as determined by the surgeon.

Arterial blood samples for determination of remifentanil concentrations were scheduled to be taken at the following points: baseline, 5 and 15 min after the start of the remifentanil infusion, immediately before sternotomy, immediately before CPB, immediately before rewarming, immediately before and immediately after separation from CPB, immediately before the downward titration of remifentanil in the intensive care unit, and at extubation (in patients extubated within 6 h after surgery). In addition, at one study site, samples were scheduled to be taken at the above times before CPB and also at 2, 5, 15, 30, and 60 min after the institution of CPB. At this site, cooling on CPB was delayed for 5 min until the 2- and 5-min samples were collected to help delineate changes in remifentanil pharmacokinetics as a result of hemodilution or hypothermia. Each blood sample was denatured with acetonitrile and promptly extracted into 4 vol of methylene chloride with separation of organic and aqueous phases. Remifentanil concentrations were determined by gas chromatography-high resolution mass spectrometry-selected ion monitoring (21). The assay was validated over the concentration range of 0.1 to 250 ng/mL. The within- and between-day percentage coefficient of variation was <15.9%.

Data were analyzed using NONMEM, a nonlinear extended least squares regression program that accounts for interpatient variability (22,23). One-, two-, and three-compartment models were considered and parameterized in terms of central volume (V1), steady-state volume (Vss), intercompartmental clearance (Clp), and elimination clearance (Cle). The influence of CPB on remifentanil disposition was described using different values of the compartment volumes, distribution clearances, elimination clearance, and volume of distribution at steady state during and after CPB, compared with those calculated for the pre-CPB period.

The influence of temperature on remifentanil elimination was modeled by assuming that Cle was an exponential function of temperature; i.e., we assumed that the typical value of clearance for the population was given by exp({theta}*[T-37]), where T is temperature and {theta} is to be estimated by NONMEM. The mechanistic justification for this assumption is the Arrhenius relationship. Temperature was not continuously recorded so it was also assumed that temperatures between recorded values could be approximated by exponential interpolation. This model (exponential relation between Cle and temperature and exponential interpolation of temperature) was analyzed by using the differential equation mode of NONMEM. This approach allows temperature to vary in a continuous manner. We also analyzed temperature effects with a discontinuous model in which NONMEM used the temperature, and hence clearance, predicted from the time of the last "event" (recorded temperature change, dose change, or concentration measurement) up to the time of the current event.

The influence of body size on drug disposition was assessed by comparing models that assumed that 1) all pharmacokinetic variables (volumes and clearances) were independent of weight, 2) that all variables were directly proportional to weight, or 3) that volumes were proportional to body weight and that clearances were proportional to body weight increased to a power of 3/4. This latter model, allometric scaling, has been proposed by Holford (24) based on fundamental biological approaches to scaling phenomena.

Interindividual variability in variable values was assumed to follow a log normal distribution, and the residual error (the difference between predicted and measured remifentanil concentrations) was modeled with a combined proportional and additive model. Estimation of variable values was performed by using NONMEM and the first-order conditional method with interaction. Individual patient pharmacokinetic variables were estimated by using the post hoc Bayesian method, as described in the NONMEM Users Guide (22). Selection of the optimal model was based on the objective function (-2 x the logarithm of the likelihood of the results) and the predictive accuracy of the model, assessed by the median absolute relative prediction error (the relative prediction error is the difference between the measured and post hoc Bayesian predicted drug concentrations as a fraction of the predicted concentration) (22,23).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Thirty patients were enrolled at Emory University Hospital and OH State University Hospital and 12 at the University of Cincinnati Medical Center. There were 431 observations (remifentanil concentrations) from 68 patients available for analysis. There was at least one remifentanil concentration measured during CPB for each patient with data available for analysis. Demographics are presented in Table 1. The majority of patients required adjustments in the remifentanil dose. Overall, 64% of patients required one or more boluses and 83% received infusion rate increases because of signs of light anesthesia. Furthermore, 68% of patients had infusion rate decreases because the signs of light anesthesia were controlled, the stimulus ended, or hypotension ensued.


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  		Table 1. Demographics
 
Pharmacokinetic analysis revealed that the single-compartment model was inferior to the two-compartment model, with an improvement in the objective function of 265 U when the two-compartment model was used. Use of a three-compartment model did not result in a further significant decrease in the objective function. Thus, the two-compartment model was used for subsequent analysis. Assuming that the pharmacokinetic variables were linearly proportional to weight improved the objective function by 10 U, in comparison with a simple model in which the influence of weight was ignored. However, using an allometric model, that assumed that V1 and Vss were proportional to weight and clearances were proportional to weight increased to a power of 3/4, resulted in a further improvement in the objective function of 4 U. Convergence for a model in which the volume of distribution did not change with the institution of CPB terminated because of rounding errors with a significantly worse (30 U) objective function. When central and peripheral volumes were allowed to increase with CPB, the magnitude of the increase in the volume of distribution was 86%. Allowing elimination and intercompartmental clearances to change during and after CPB (independently of temperature effects) did not significantly improve the quality of the fit. Allowing volumes to change again after CPB, including allowing Vss to return to the pre-CPB value, did not significantly improve the fit.

The differential equation analysis for a temperature effect on Cle failed to converge. However, the discontinuous method of analysis did converge. Modeling Cle as an exponential function of temperature (the temperature range was 20°–35°C) resulted in an improvement in the objective function of 223 U which is highly significant. There was a proportional decrease of 6.37% in Cle with each degree (Celsius) decrease in temperature below 37°C.

The variables of the optimal pharmacokinetic model are presented in Table 2. The median absolute relative prediction error (the median of the absolute values of the difference between measured and post hoc Bayesian predicted concentrations, expressed as a percentage of the predicted concentration) for all data points was 17.5%. A plot of relative prediction error versus time for all data points is shown in Figure 1. There were 21 patients who had multiple (>=5) samples drawn during CPB. The median absolute relative prediction error for the individual patients in this group ranged from 6.9% to 162% with a median value (the median of the medians) of 21.4%. In Figure 2, we present the relationships between measured and predicted concentrations for the patients with the worst, median, and best individual median absolute relative prediction error.


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  		Table 2. Pharmacokinetic Variables
 


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  		Figure 1. Relative prediction error as a function of time. Cp is the post hoc Bayesian predicted remifentanil concentration and Cm is the measured concentration.

 


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  		Figure 2. The relationship between measured and predicted concentration (denoted C on the ordinates) for selected patients who had delayed cooling and frequent sampling during CPB. The closed diamonds are measured concentrations and the solid lines are predicted concentrations. The selected patients were those who had the worst, median, and best values of median absolute relative prediction error.

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The most significant observations of this study are that Cle decreases with hypothermia and that the volume of distribution increases with the institution of CPB. The former observation is intuitive, because remifentanil is metabolized by blood and tissue esterases, and we would expect enzyme activity to decrease with decreasing temperature. The model we used to analyze the temperature effect was approximate. Our variable estimates are based on a model in which the effect of temperature on clearance was solved in an aggregate manner with the pharmacokinetic model being updated from one event to the next (an event is either a dose change, temperature change, or concentration measurement). The effect of hypothermia on Cle that we observed by using this model is more than that of a previous report of a 20% decrease in Cle during hypothermic bypass at 28°–30°C (25). This earlier study specifically focused on the effects of hypothermia by administering a bolus dose of remifentanil after 15 minutes of hypothermia on CPB and then determining blood concentrations of remifentanil over 30 minutes. Sufficient samples were drawn from each patient to determine pharmacokinetic variables for each individual. A priori, this study design should be more informative about the effects of hypothermia. However, the number of subjects and number of data points are significantly larger in our study. Furthermore, in the two-stage analysis used by Russell et al. (25), the mean clearance for hypothermia is a simple average of the individual values. Each of these individual values is actually an estimate with its own confidence intervals. Simple averaging does not take into account that some individual estimates of clearance are more reliable than others, as population analysis does.

We observed the expected decrease in remifentanil concentrations with the institution of CPB, manifested in an 86% increase in the Vss of distribution. This presumably reflects hemodilution. The effect on free remifentanil concentrations is unknown because we did not study protein binding. However, the magnitude of the increase in Vss is far larger than what we would expect for an adult with a normal intravascular blood volume (approximately 5 L) diluted by a typical CPB circuit volume (approximately 2 L). The increase may also reflect the hemodiluting effects of multiple doses of cardioplegia. We must also point out that our estimate of central compartment volume was only 1.58 L for a 70-kg patient. This is quite small in comparison to estimates from previous studies, which have ranged from approximately 4–10 L (12–15,25). Estimation of compartment volumes can be quite sensitive to sampling times. In this study, relatively few samples were drawn in the early phases of drug administration, but there was a subset of patients with relatively dense sampling after institution of CPB. We cannot eliminate the possibility that our estimate of V1 before CPB is relatively inaccurate because of sparse sampling and more accurate after institution of CPB because of denser sampling. Thus, the large percentage increase in volumes with the institution of CPB may simply reflect this inaccuracy.

Two other aspects of our development of a pharmacokinetic model that contrast with previous studies should be noted. First, previous investigators have reported that a three-compartment model is optimal for describing the pharmacokinetics of remifentanil (12,14) in contrast to our two-compartment model. This may reflect our study design, which used a continuous infusion and did not have ample sampling during a washout phase. Second, we accounted for body mass as a covariate by assuming that compartment volumes were proportional to weight whereas clearances (distribution and elimination) were proportional to weight increased to a power of 0.75 (the allometric model). We initially found that simply assuming that all pharmacokinetic variables were proportional to weight significantly improved the fit of the model to the data. However, the slightly more complex allometric model resulted in a further small, but statistically significant, improvement in the objective function. Egan et al. (26), in a comparative study of lean and obese patients, found an optimal model in which selected variables (Cle, central and peripheral distribution volumes) were proportional to lean body mass. We did not elect to sequentially analyze the role of either weight or lean body mass on individual variables because the range of weights in this study was much smaller than in the study by Egan et al. It should be noted that the ability to empirically determine the influence of covariates (as in the study by Egan et al.) is not a capability of NONMEM. Rather it is primarily an issue of the data that are available. With a relatively narrow range of weights it is not possible to investigate the issue in depth or to reject the null hypothesis. We adopted the allometric model because it has a sound biological/mechanistic basis, as discussed by Holford (24) and Anderson et al. (27).

The clinical implications of our results are illustrated in Figure 3. This figure presents simulated remifentanil concentrations for two hypothetical 70-kg patients receiving an infusion of remifentanil at 1 µg · kg-1 · min-1 for 60 minutes, at which time CPB is instituted with cooling and maintenance of temperature at 32° or 27°C. With CPB, there is an immediate decrease in remifentanil concentration because of hemodilution. In the patient cooled to 27°C, there is very rapid recovery (within five minutes) to pre-CPB levels because of decreased clearance. The remifentanil concentration then increases for the duration of time on CPB. For the patient cooled to 32°C, recovery to pre-CPB levels is more prolonged, requiring approximately 25 minutes. These simulations imply that, for moderate hypothermia, the infusion rate of remifentanil can be decreased almost immediately after the institution of CPB. For mild hypothermia, the infusion rate may be decreased after approximately 20–30 minutes. More constant blood levels may be obtained by decreasing the infusion rate approximately 30% for each 5°C decrease in temperature.



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  		Figure 3. Simulated concentrations of remifentanil using the pharmacokinetic variables presented in Table 2. For these simulations it was assumed that the patients received an infusion of remifentanil at 1 µg · kg-1 · min-1 for 60 min, at which time cardiopulmonary bypass (CPB) was instituted with cooling to 32°C (lower curve) or 27°C (upper curve) and the patients were maintained at these temperatures on CPB for 90 min without a change in remifentanil dose.

 

   Acknowledgments
 
This research was funded by a grant from Glaxo, Inc.

The authors gratefully acknowledge the assistance of Michael Howie of the Ohio State University Hospital and David Poremka of the University of Cincinnati Medical Center in the collection of blood samples for pharmacokinetic analysis.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Accepted for publication June 7, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press